The invention describes composition and methods of preventing HIV infection using a truncated version of the HIV gp41 subunit of Env fused to human Fc through a flexible linker as a vaccine immunogen.  This immunogen binds several broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies recently identified and developed by the inventor’s laboratory, including m44.  m44 does not react with self-antigen suggesting that this immunogen may elicit antibodies which are not regulated by tolerance mechanisms, a problem suggested as the cause of failure for some of the gp41-based immunogens previously tested.  Rabbits immunized with this fusion construct developed broad-neutralizing antibodies against several HIV-isolates from different clades in a cell line/pseudovirus assay with high titer.  Preclinical testing of these novel immunogens in primate models is currently being planned.

Applications:

Treatment and prevention of HIV infection

Advantages:

• Has potential to elicit broad neutralizing antibodies against several HIV isolates from different clades
• Immunogen is based on the gp41 subunit of the HIV Env, a region more conserved than the gp120 subunit of Env and fusion to Fc increases the stability and half-life of the immunogen
• Potentially elicits antibodies that are not regulated by tolerance mechanisms

Development Status:

Data can be provided upon request

Publications:

1. M-Y Zhang, V Choudhry, IA Sidorov, V Tenev, BK Vu, A Choudhary, H Lu, GM Stiegler, HWD Katinger, S Jiang, CC Broder, DS Dimitrov.  Selection of a novel gp41-specific HIV-1 neutralizing human antibody by competitive antigen panning.  J Immunol Methods 2006 Dec 20;317(1-2):21-30.  [PubMed abs]
2. M-Y Zhang, DS Dimitrov.  Novel approaches for identification of broadly cross-reactive HIV-1 neutralizing human monoclonal antibodies and improvement of their potency.  Curr Pharm Des. 2007;13(2):203-212.  [PubMed abs]
3. V Choudhry, M-Y Zhang, IA Sidorov, JM Louis, I Harris, AS Dimitrov, P Bouma, F Cham, A Choudhary, SM Rybak, T Fouts, DC Montefiori, CC Broder, GV Quinnan, DS Dimitrov.  Cross-reactive HIV-1 neutralizing monoclonal antibodies selected by screening of an immune human phage library against an envelope glycoprotein (gp140) isolated from a patient (R2) with broadly HIV-1 neutralizing antibodies.  Virology 2007 Jun 20;363(1):79-90.  [PubMed abs]
4. M-Y Zhang, BK Vu, A Choudhary, H Lu, M Humbert, H Ong, M Alam, RM Ruprecht, G Quinnan, S Jiang, DC Montefiori, JR Mascola, CC Broder, BF Haynes, DS Dimitrov. Cross-reactive human immunodeficiency virus type 1-neutralizing human monoclonal antibody that recognizes a novel conformational epitope on gp41 and lacks reactivity against self-antigens. J Virol. 2008 Jul;82(14):6869-6879.  [PubMed abs]

U.S. Provisional Application No. 61/126,662 filed 06 May 2008 (HHS Reference No. E-072-2008/0-US-01)

Inventors:

Dimiter S. Dimitrov and Mei-yun Zhang (NCI)

Licensees Sought:

Available for exclusive or non-exclusive licensing.

Collaborative Research Opportunity:

The National Cancer Institute CCR Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology.  Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.